Cryptococcal meningitis (CM) is the AIDS-associated opportunistic infection that causes the largest number of deaths worldwide. The CDC estimates that approximately one million new cases of CM occur each year, with 70% of these new cases occurring in sub-Saharan Africa. Currently, 60% of patients with CM die within 3-6 months. Although use of antiretroviral therapy (ART) improves outcomes, many CM patients who start ART exhibit paradoxical deterioration in their clinical status because of HIV immune reconstitution inflammatory syndrome (IRIS). IRIS causes clinical worsening in these patients due to exaggerated inflammatory responses to Cryptococcus neoformans. In patients with CM, IRIS manifestations include relapsing meningitis, increased intracranial pressure, new focal neurological signs, development of lymphadenopathy, intracranial cryptococcomas, pneumonitis, or cryptococcal abscesses. Our preliminary data from Ugandan AIDS patients suggest that IRIS occurs in approximately 50% of patients with CM after initiation of ART, causing death in approximately 25% of patients with CM. This grant proposes to extend my collaborative research program related to CM in Uganda and to use this research program as a venue to provide mentorship in international patient-oriented research to physician-scientist trainees from the United States and Uganda. The specific aims of the research plan are 1) to conduct a multi-site randomized trial among 500 persons with CM in sub- Saharan Africa to compare early ART initiation (within 2 weeks of CM diagnosis) to standard ART initiation (4-5 weeks after CM diagnosis) with respect to 26 week mortality (primary outcome), incidence and severity of CM IRIS, HIV virological suppression, microbiological clearance of cryptococcus, and ART tolerability, 2) to assess long-term neurological outcomes among survivors of CM to determine if persons who develop IRIS after initiation of ART have worse outcomes compared to those who do not develop IRIS, and 3) to determine if inflammatory biomarkers in blood or CSF of patients with CM can predict outcomes such as mortality, IRIS, or long-term neurological deficits. The mentorship plan includes 1) primary mentorship to junior faculty and infectious diseases fellow trainees who will work on this project and 2) leadership of mentorship programs in patient- oriented research for junior faculty and infectious diseases fellows at the University of Minnesota. Project Narrative: Cryptococcal meningitis (CM) is the AIDS-associated opportunistic infection that causes the largest number of deaths worldwide. The CDC estimates that approximately one million new cases of CM occur each year, with 70% of these new cases occurring in sub-Saharan Africa. Although AIDS treatment is necessary for patients with CM to survive, many CM patients who start AIDS treatment become sicker or die due to HIV immune reconstitution inflammatory syndrome (IRIS), an inflammatory reaction that occurs as the immune system improves after starting AIDS therapy. The goals of this study are 1) determine if starting AIDS therapy shortly after the diagnosis of CM will improve survival by improving the ability of the immune system to fight the cryptococcal infection or cause more deaths due to IRIS, 2) determine if survivors of CM with or without IRIS have neurological impairment, and 3) develop laboratory tests that could be used to diagnose IRIS and predict which patients are at risk so they can be treated before they become ill. By participating in this research, physician-scientist trainees from the United States and Uganda will learn about international AIDS research and gain experience that will help them become the next generation of international AIDS research leaders.